Phosphonoformates, antiviral activity

Foscarnet (trisodium phosphonoformate) is an inorganic pyrophosphate analog, which inhibits many DNA polymerases, retroviral reverse transcriptase, and some RNA polymerases, and has antiviral activity against all of the herpes viruses and HIV. Foscarnet... 

Lambert, R.W., Martin, J.A., Thomas, G.J., Duncan, I.B., Hall, M.J., and Heimer. E.P., Synthesis and antiviral activity of phosphonoacetic and phosphonoformic acid esters of 5-bromo-2 -deoxyuridine and related pyrimidine nucleosides and acyclonucleosides, J. Med. Chem., 32. 367, 1989. 

CHEMISTRY AND ANTIVIRAL ACTIVITY Foscarnet (trisodium phosphonoformate) is an inorganic pyrophosphate analog that inhibits herpesviruses and HIV. 

Some aromatic thiosemicarbazones are active against smallpox virus, while phosphonoformic acid (PFA) and phosphonoacetic acid (PAA) are active against herpes viruses. Consequently, some acylphosphonate thiosemicarbazones, (47), in which the two types of structural moieties appear together, were synthesized and tested for antiviral activity. However, no inhibitory activity was observed against herpes and/or pox viruses . 

Mechanisms Foscarnet is a phosphonoformate derivative that does not require phosphorylation for antiviral activity. Though it is not an anti metabolite, foscarnet inhibits viral RNA polymerase, DNA polymerase, and HIV reverse transcriptase. A known mechanism of resistance involves point mutations in the DNA polymerase gene. 

A range of triesters (24) and diesters (25) of the antiviral phosphonofor-mate has been synthesized. Compounds with simple alkyl groups showed no antiviral activity, which was attributed to their inability to undergo complete hydrolysis to phosphonoformate. In contrast, the more labile phenyl esters were active against HSV-1, with the triphenyl (24, R = Ph) and diphenyl (25, R = Ph) esters giving IC50 values of 39 and 52 /zM, respectively [38]. 

Phosphonoformate is a pyrophosphate analog and inhibits both DNA polymerases and reverse transcriptase. However, toxicity may prevent longterm treatment of AIDS patients. Amantadine has a narrow antiviral specificity. It specifically inhibits initiation of the replication of influenza virus RNA of type A (but not of type B). Active only against retroviruses, 3 -azidothymidine is a reverse transcriptase inhibitor, which acts by a chain termination mechanism. It was synthesized in the early 1960s but only recently has been used in treatment of AIDS victims. More recently a series of 2, 3 -dideoxynucleosides, such as dideoxyinosine, have also been used.d Acyclic phosphonates, such as phosphonylmethoxypropyladenine, avoid the need for metabolic phosphorylation of the drug.6... 

Phosphonoformic acid (Foscarnet), an antiviral drug, which consists of carboxylic acid and phosphate linked together, was shown to be absorbed in the small intestine by the phosphate carrier-mediated mechanism [154], The transport of folic acid was investigated in biopsy specimens of intestinal mucosa from healthy volunteers. A pH-dependent, active transport of folic acid was found in the proximal small intestine, whereas in the mucosa of the colon, folic acid uptake was driven by a facilitated diffusion, mediated by a low-affinity carrier [155]. The existence of folate receptors in the human colonic mucosa is logical due to the large amounts of folic acid produced by the colonic flora [145],... 

A substantial number of phosphonates have been prepared and tested against viral infections, including AIDS. Even relatively simple compounds such as the above-mentioned phosphonoformic acid (19, = 0) and phosphonoacetic acid (19, n= 1) were reported as antivirals and herpes virus inhibitors active against acyclovirresistant herpes and cytomegalovirus retinitis in patients with AIDS . The veterinary use has been mentioned ... 

These two compounds may possess some clinical advantage over ara-A due to their low systemic toxicity. The antiviral effects of phosphonoformic acid (PFA, foscarnet sodium), which is presently in Phase III clinical trials in Europe, 3 have been discussed in a recent review.91 The synthesis and structural requirements for antiherpes activity of a series of PFA esters have also been reported.92... 

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